寻求靶向治疗对于对抗癌症至关重要。 RAS/MAP 激酶通路经常与肿瘤形成有关，其中 ERK 作为 RAS 信号级联中最远端的激酶发挥着至关重要的作用。我们之前的研究表明，ERK 和先天免疫中的接头蛋白 MYD88 之间的相互作用对于 RAS 依赖性转化和癌细胞存活至关重要。在这项研究中，我们研究了通过 ERK D 募集位点 (DRS) 破坏 ERK-MYD88 相互作用，同时保留 ERK 激酶活性的生物学后果。我们的结果表明，EI-52（一种靶向 ERK-MYD88 相互作用的小分子苯并咪唑）可诱导 HRI 介导的整合应激反应 (ISR)，从而导致癌细胞特异性的免疫原性凋亡。此外，EI-52 在患者源性肿瘤中表现出抗肿瘤功效，并在小鼠体内诱导抗肿瘤 T 细胞反应。这些发现表明，抑制 ERK-MYD88 相互作用可能是癌症治疗中一种有前途的治疗方法。© 2024。作者。

The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.© 2024. The Author(s).